Prostate cancer is the most frequently diagnosed cancer in men in the United States. The risk of prostate cancer is 1 in 6, but the vast majority of men will not die from their cancer and many clinicians now agree that prostate cancer is over-treated. A key clinical question that remains is how to determine which patients have clinically-insignificant disease and could therefore be spared unnecessary and potentially harmful therapy. In order to identify markers for clinically-indolent tumors, a better understanding of the molecular mechanisms of clinically-indolent prostate cancer is needed. We had previously reported 3 unrecognized molecular subtypes of prostate cancer based on distinct patterns of gene expression, one of which was associated with clinically-indolent features. Further analysis with array-based comparative genomic hybridization (array CGH) has revealed a specific deletion within chromosome cytoband 6q15to be associated with clinically-indolent tumors. The overall goal of this study is to gain understanding of the molecular pathogenesis of clinically-indolent prostate cancer. Our specific objective is to identify and functionally characterize the pathogenic tumor suppressor gene (TSG)at 6q15associated with indolent- prostate cancer. Array CGH on whole-genome oligonucleotide arrays will be used to genomically profile 50 additional clinically-indolent tumor specimens to narrow down the number of genes within the 6q15deletion core to less than 10. Remaining candidate TSGs will be screened for DMA mutation by sequencing the remaining allele of tumor specimens with a single-copy deletion, and for promoter hypermethylation by sequencing the bisulfite-modified DNA from the CpG island region from tumor specimens. The functions of candidate TSGs will then be preliminarily characterized by re-expressing them in prostate cancer cell lines with the deletion and assaying the effect on cancer cell activities, including proliferation, invasiveness, and apoptosis. This study will further our knowledge of the molecular pathogenesis of clinically-indolent prostate cancer and may suggest novel gene-based markers for the diagnosis of clinically-indolent tumors. This may provide doctors with an improved ability to clinically manage and choose the best treatment for men with prostate cancer.